NM_017777.4(MKS1):c.1450_1453dup (p.Thr485fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 10, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001063563.5

Allele description [Variation Report for NM_017777.4(MKS1):c.1450_1453dup (p.Thr485fs)]

NM_017777.4(MKS1):c.1450_1453dup (p.Thr485fs)

Gene:

MKS1:MKS transition zone complex subunit 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

17q22

Genomic location:

Preferred name:

NM_017777.4(MKS1):c.1450_1453dup (p.Thr485fs)

HGVS:

NC_000017.11:g.58206504_58206507dup
NG_013020.1:g.18777_18780dup
NG_013032.1:g.18101_18104dup
NM_001321268.2:c.841_844dup
NM_001321269.2:c.1408-125_1408-122dup
NM_001330397.2:c.1274-125_1274-122dup
NM_017777.4:c.1450_1453dupMANE SELECT
NP_001308197.1:p.Thr282fs
NP_060247.2:p.Thr485fs
NP_060247.2:p.Thr485fs
LRG_687t1:c.1450_1453dup
LRG_687:g.18101_18104dup
LRG_687p1:p.Thr485fs
NC_000017.10:g.56283862_56283863insTGCC
NC_000017.10:g.56283865_56283868dup
NM_017777.3:c.1450_1453dup
NM_017777.3:c.1450_1453dupGGCA
NM_017777.4:c.1450_1453dup

Protein change:

T282fs

Links:

dbSNP: rs386834044

NCBI 1000 Genomes Browser:

rs386834044

Molecular consequence:

NM_001321268.2:c.841_844dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_017777.4:c.1450_1453dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001321269.2:c.1408-125_1408-122dup - intron variant - [Sequence Ontology: SO:0001627]
NM_001330397.2:c.1274-125_1274-122dup - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Familial aplasia of the vermis
Synonyms:: CEREBELLOPARENCHYMAL DISORDER IV; Joubert syndrome; Cerebelloparenchymal disorder 4; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018772; MedGen: C0431399; Orphanet: 475; OMIM: PS213300

Name:: Meckel-Gruber syndrome
Synonyms:: DYSENCEPHALIA SPLANCHNOCYSTICA; Gruber syndrome; Dysencephalia splachnocystica
Identifiers:: MONDO: MONDO:0018921; MedGen: C0265215; OMIM: PS249000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001228414	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 10, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17185389, 17397051, 26490104, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001228414

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 10, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation.

Dawe HR, Smith UM, Cullinane AR, Gerrelli D, Cox P, Badano JL, Blair-Reid S, Sriram N, Katsanis N, Attie-Bitach T, Afford SC, Copp AJ, Kelly DA, Gull K, Johnson CA.

Hum Mol Genet. 2007 Jan 15;16(2):173-86. Epub 2006 Dec 21.

PubMed [citation]

PMID:: 17185389

Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. Mutation in brief #960. Online.

Khaddour R, Smith U, Baala L, Martinovic J, Clavering D, Shaffiq R, Ozilou C, Cullinane A, Kyttälä M, Shalev S, Audollent S, d'Humières C, Kadhom N, Esculpavit C, Viot G, Boone C, Oien C, Encha-Razavi F, Batman PA, Bennett CP, Woods CG, Roume J, et al.

Hum Mutat. 2007 May;28(5):523-4.

PubMed [citation]

PMID:: 17397051

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001228414.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change results in a frameshift in the MKS1 gene (p.Thr485Argfs*107). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acid(s) of the MKS1 protein and extend the protein by 31 additional amino acid residues. This variant is present in population databases (rs386834044, gnomAD 0.06%). This frameshift has been observed in individual(s) with Meckel Gruber syndrome (PMID: 17185389, 17397051). This variant is also known as c.1448_1451dupCAGG; p.G484fsX108. ClinVar contains an entry for this variant (Variation ID: 56617). This variant results in an extension of the MKS1 protein. Other variant(s) that result in a similarly extended protein product (p.Arg510Profs*81) have been observed in individuals with MKS1-related disease (PMID: 26490104). This suggests that these extensions may be clinically significant. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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